The present invention is directed to methods for preventing the development of and treating dyskinesias in patients being treated for Parkinson""s disease utilizing substituted phenylazacycloalkanes and dopamine agonists.
Parkinson""s disease is pathologically associated with a degeneration within the nuclear masses of the extrapyramidal system and the characteristic loss of melanin-containing cells from the substantia nigra and a corresponding reduction in dopamine levels in the corpus striatum. A conventional method of treating Parkinson""s disease involves the administration of a dopamine agonist to a patient suffering from this disorder to restore the nigro-neostriatal hypofunction by increasing the post synaptic dopamine receptor stimulation. However, when a dopamine agonist such as L-DOPA is used to treat Parkinson""s disease, typically, dyskinesias occur in the patient as a side effect. These dyskinesias usually occur at the peak dosage and may assume one or more of several possible forms such as choreic, dystonic, athetotic or myoponic with varying intensities and sometimes occurs to such an extent that it is worse than the underlying Parkinsonism. It is believed that the development of L-DOPA induced dyskinesias result from severe nigrostriatal denervation in combination with chronic L-DOPA treatment for a period of time of months to years. Once the dyskinesias manifest themselves, the therapeutic options that can be offered to the patient are reduced.
Freed et al in N Engl J Med, Vol. 344, No. 10, Mar. 8, 2001, pages 710-719, proposes the treatment of Parkinson""s disease by transplanting human embryonic dopamine neurons into the brains of patients with Parkinson""s disease as a method of raising dopamine levels in the corpus striatum and alleviating the effects associated with Parkinson""s disease. This method of treatment was shown to be successful in some patients in reducing the symptoms and signs of Parkinson""s disease but had problems of the development of dystonias and dyskinesias after the transplantation of the embryonic dopamine neurons, even after a substantial reduction in or elimination of therapy with dopamine-agonist drugs.
U.S. Pat. No. 5,462,947 to Svensson et al discloses substituted phenylazacycloalkanes which possess selective dopamine receptor pharmacological properties and are useful in treating central nervous system disorders such as depression symptoms, geriatric disorders, schizophrenia, narcolepsy, MBD, obesity, disturbances of sexual functions, and rehabilitation of drug abusers.
Ekesbo et al in Neuro Report, Vol. 8, No. 11, Jul. 28, 1997, pages 2567-2570, teaches the use of S-(xe2x88x92)-3-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine attenuating L-DOPA-induced contraversive turning behavior in unilaterally dopamine-lesioned monkeys.
Ekesbo et al in Eur. J. Pharmacol. (2000), 389 (2/3), 193-199, discloses that treatment with S-(xe2x88x92)-3-[3-(methylsulfonyl) phenyl]-1-propyl-piperidine attenuated rotational behavior induced by apomorphine, L-DOPA and quinpirole without inducing motor impairment such as akinesia or dystonia.
Waters et al in WO 99/03470 discloses the use of specified substituted 3-phenylpiperidines and 3-phenylpyrolidine analogs for treating impaired cognitive functions for patients suffering from dementia, schizophrenia, bi-polar disease, attention deficit disorders, hyperactivity disorders and neurological disorders such as Parkinson""s and Huntington""s diseases.
Waters et al in WO 00/03714 discloses specific substituted 3-phenylpiperidines and 3-phenylpyrolidine analogs for the treatment of dyskinesias such as dystonias, tremor and chorea and Huntington""s disease.
The present invention is directed to a method for preventing the development of and treating dyskinesias resulting from the treatment of a patient suffering from Parkinson""s disease which comprises a step of administering a substituted phenylazacycloalkane compound according to formula (I). 
wherein n is 1 or 2; R1 and R2 are independently H, provided that both are not H, xe2x80x94OH, CN, CH2CN, 2- or 4-CF3, CH2CF3, CH2CHF2, CHxe2x95x90CF2, (CH2)2CF3, ethenyl, 2-propenyl, OSO2CH3, OSO2CF3, SSO2CF3, COR, COOR, CON(R)2, CONH2, SOxCH3, SOxCF3, O(CH2)xCF3, where x is 0-2, SO2N(R)2, CHxe2x95x90NOR, COCOOR, COCOON(R)2, C1-8 alkyls, C3-8 cycloalkyls, CH2OR, CH2(R)2, NRSO2CF3, NO2, halogen, phenyl in positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine;
R3 is hydrogen, CF3, CH2CF3, C1-8 alkyl, C3-8 cycloalkyl, C4-9 cycloalkyl-methyl, C2-8 alkenyl, C2-8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, xe2x95x90(CH2)mxe2x80x94R5, where m is 1-8, CH2SCH3 or a C4-8 alkylene bonded to the N-atom and one of its adjacent carbon atoms to form a heterocyclic structure;
R4 and R are independently selected from hydrogen, CF3, CH2CF3, C1-C8 alkyl, C3-8 cycloalkyl, C4-9 cycloalkyl-methyl, C2-8 alkenyl, C2-8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, or xe2x80x94(CH2)mxe2x80x94R5, where m is 1-8;
R5 is phenyl, phenyl substituted with CN, CF3, CH2CF3, C1-8 alkyl, C3-8 cycloalkyl, C4-9 cycloalkyl-methyl, C2-8 alkenyl or C2-8 alkynyl, 2-thiophenyl, 3-thiophenyl, xe2x80x94NR6CONR6R7 or CONR6R7; and
R6 and R7 are independently hydrogen, C1-8 alkyl, C3-8 cycloalkyl, C4-9 cycloalkyl-methyl, C2-8 alkenyl or C2-8 alkynyl.
The compounds of formula (I) can be provided in both the racemic mixtures and the pure R or S enantiomers. The preferred compounds have the S absolute configuration according to the Cahn-Ingold-Prelog priority rules and, depending on the N-substituents, may be dextrorotatory or levorotatory.
In one preferred embodiment of the present invention, the compound of formula (I) is S-(xe2x88x92)-3-[3-(methylsulfonyl) phenyl]-1-propyl-piperidine, which can be provided in the form of a pharmaceutically acceptable salt, such as a hydrochloride salt.
The present invention provides a method for preventing the development of dyskinesias in a patient being treated for Parkinson""s disease through the use of a dopamine agonist without inducing akinesia or reducing the anti-Parkisonian efficacy of the dopamine agonist. Another aspect of the present invention provides a method for treating dyskinesias developed in a patient being treated for Parkinson""s disease through the use of a dopamine agonist without reducing the anti-Parkinsonian efficacy of the dopamine agonist. The compound of formula (I) can be administered concomitantly with the dopamine agonist or before or after the administration of the dopamine agonist. xe2x80x9cConcomitantlyxe2x80x9d is defined to mean within the same treatment period as the administration of the dopamine agonist which is preferably within twelve hours and up to forty-eight hours from the administration of the dopamine agonist. xe2x80x9cPreventionxe2x80x9d means preventing the appearance of dyskinesias or reducing the progression of severity of already established dyskinesias.
In another preferred embodiment of the present invention, the dopamine agonist is L-DOPA.
The present invention also provides a method for the treatment or prevention of dyskinesias in a patient treated for Parkinson""s disease by the transplantation of dopamine neurons into the brain of the patient through the administration of the compound of formula (I). Patients undergoing such transplantations can also be treated with different neurotrophic factors to facilitate neuronal growth. The compound of formula (I) can be administered after the transplantation has occurred either solely or in combination with a dopamine agonist. When the compound of formula (I) is administered in combination with a dopamine agonist, it can be administered within the same treatment period as the administration of the dopamine agonist, which is preferably within twelve hours and up to forty-eight hours from the administration of the dopamine agonist.